Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications referenced by number in the specification are set forth at the end of the specification.
Macrophages stand as gatekeepers in the host immune defense against invading bacteria due to their rich array of antimicrobial devices. While macrophages can internalize a variety of intruding microbes through phagocytosis and degrade them within phagolysosomes, pathogenic mycobacteria have developed creative means to avoid the fatal fusion with lysosomes, and successfully multiply within these structures (Rhoades, E. R. & Ullrich, H. J., 2000, Immunology and Cell Biology 78: 301-310; Pieters, J., 2001, Microbes and Infection 3: 249-255; Chua, J. et al., 2004, Current Opinion in Microbiology 7: 71-77).
Mycobacterium tuberculosis, one of the most serious macrophage-targeted pathogens, currently infects one third of the world's population and increasing reports of multi-drug resistant tuberculosis (MDR-TB) further threaten TB control efforts (World Health Organization tuberculosis fact sheet: see worldwide web url at int/mediacentre/factsheets). M. avium and M. tuberculosis are also a growing problem for HIV patients.
Iron is an essential element for both hosts and bacterial pathogens due to its central role in a variety of metabolic pathways (Ratledge, C. & Dover, L. G., 2000, Annual Review of Microbiology 54: 881-941; Hentze, M. W. et al., 2004, Cell 117: 285-297). Consequently, restricting the availability of iron is an important defense against bacterial infection. Among the various strategies adapted by human for this purpose are the increased synthesis of ferritins (Weiss, G. et al., 1995, Immunology Today 16: 495-500; Byrd, T. F. & Horwitz, M. A., 1993, Journal of Clinical Investigation 91: 969-976), the withdrawal of iron from serum transferring (Torti, S. V. et al., 1988, Journal of Biological Chemistry 263: 12638-12644), and the secretion of lipocalins to scavenge microbial siderophores (Goetz, D. H. et al., 2002, Molecular Cell 10: 1033-1043; Fluckinger, M. et al., 2004, Antimicrobial Agents and Chemotherapy 48: 3367-3372). Even in the face of these defenses, pathogenic mycobacteria do gain sufficient iron for growth while residing within phagosomes (Ratledge et al., 2000, supra; Ratledge, C., 2004 Tuberculosis 84: 110-130; Olakanmi, O. et al., 2002, Journal of Biological Chemistry 277: 49727-49734). This observation suggest that mycobacteria must successfully circumvent these host iron restrictions.
In vitro, pathogenic mycobacteria secrete two classes of iron chelating agents, known as siderophores: water-soluble carboxymycobactins and lipophilic mycobactins, which are responsible for extracellular iron transport to the bacteria (Crosa, J. H. & Walsh, C. T., 2002, Microbiology and Molecular Biology Reviews 66: 223-249; De Voss, J. J. et al., 1999, Journal of Bacteriology 181: 4443-4451). Recent studies indicate that liphophilic mycobactins are essential for the iron access and transport of macrophage-niched mycobactria (De Voss, J. J. et al., 2000; Proceedings of the National Academy of Sciences USA 97: 1252-1257). However, little is known about the iron acquisition and transport pathways adapted by mycobacteria in vivo.
Elucidating and exploiting the mechanisms of virulent mycobacterial pathology to develop new approaches to combating these infections are of urgent concern to world health care. There is an ongoing need for new biological targets for the rational design of antibacterial agents, as well as screening methods for identifying and testing candidate compounds, and thereafter developing new methods and agents for the treatment of mycobacterial infection.